Cerebrovascular attack (CVA) or stroke is the third cause of death and the most common cause of permanent disability in the world. Stroke is a sudden interruption in the blood supply to the brain. About 80% of strokes are caused by an abrupt blockage of arteries leading to the brain (ischemic stroke). Other strokes are caused by bleeding into the brain tissue due to a blood vessel burst (hemorrhagic stroke). Ischemic strokes can further be divided into thrombotic and embolic strokes. Thrombotic strokes occur when a brain artery is blocked by a blood clot formed in the brain and account for approximately 50% of all strokes. Embolic strokes are caused by a thrombus, which is formed in a peripheral artery that travels to the brain where it produces ischemia. Other causes of reduction of brain blood flow are: perforating artery occlusion, intracranial artery stenosis with poor collateral circulation, arteritis, arterial dissection, venous occlusion, and anemia or significant hyperviscosity.
So far, the only treatment for ischemic stroke during arterial occlusion phase is the use of thrombolytic agents to recover brain perfusion. Particularly, the intravenous administration of tissue plasminogen activator (tPA) is the choice treatment for patients who have suffered an ischemic stroke. However, often, patients who have suffered a stroke and are treated with thrombolytic therapy suffer from the so-called “hemorrhagic transformation” (HT), which is characterized by a process of blood extravasations involving a high morbidity and mortality. Therefore, in order to facilitate the selection of patients so that they can benefit to a great extent from treatment with t-PA, it is necessary to identify those patients at high risk of suffering hemorrhagic transformation. Surnii T et a (Stroke, 2002; 33:831-836) and Montaner J et al. (Circulation, 2003, 107:598-603) have reported that patients having high risk of suffering hemorrhagic transformation show elevated levels of matrix metalloproteinase-9 (MMP-9) so that determination of MMP-9 levels can be used to predict the probability of hemorrhagic complications after thrombolytic therapy for stroke.
Millán et al (Stroke, 2007, 38:90-95) have reported that elevated intracorporeal iron and ferritin levels are correlated with a worse prognosis in patients who have suffered stroke and with a higher risk of suffering hemorrhagic transformation after thrombolytic therapy.
WO2006036220 describes that increased plasma levels of cellular fibronectin (c-Fn) are correlated with a worse prognosis in patients who have suffered stroke and with a higher risk of suffering hemorrhagic transformation after thrombolytic therapy.
Moreover, it has been demonstrated that patients who suffered hemorrhagic transformation presented lower levels of plasminogen activator inhibitor 1 (PAI-1) and higher levels of thrombin activable fibrinolysis inhibitor (TAFI), and that the combination of PAI-1<21.4 ng/mL and TAFI>180% levels had the best sensitivity and specificity for predicting the appearance of hemorrhagic complications (Ribóo et al, 2004, Stroke 35:2123-2127).
However, the use of MMP-9, cellular fibronectin and/or endogenous fibrinolysis inhibitors as markers for hemorrhagic transformation risk requires measurement of said protein expression levels, which usually requires an analysis time longer than that recommended to start thrombolytic therapy.
In addition, it has been reported that S100B protein may be used to determine the risk of hemorrhagic complications after thrombolytic therapy (Foerch, et al., 2007, Stroke, 38:2491-2495). However, the diagnostic sensitivity by using S100B levels as the only marker was rather low for this marker to be used as a reliable marker in clinical practice.
Therefore, there is a need for additional markers that allow predicting the propensity to suffer hemorrhagic transformation in patients who have suffered stroke and have been treated with thrombolytic therapy and, particularly, biomarkers that can be more rapidly determined since thrombolytic treatment provides better results when applied shortly after the stroke episode.